Pharmaceutical compositions for the oral administration of heparin or derivatives thereof

ABSTRACT

Pharmaceutical compositions suitable for the oral administration of heparin or derivatives thereof, particularly con-trolled-release oral pharmaceutical compositions containing heparin with different molecular weight, for the treatment of inflammatory bowel diseases and related conditions, are disclosed.

The present invention relates to pharmaceutical compositions suitablefor the oral administration of heparin or derivatives thereof for thetreatment of inflammatory bowel diseases.

More particularly, the invention relates to controlled-release oralpharmaceutical compositions containing heparin (either unfractioned orlow molecular weight heparins) capable of selectively releasing theactive ingredient in the intestine.

Chronic inflammatory bowel diseases (IBD), such as ulcerative colitisand Crohn's disease, involve therapeutical problems which have still tobe satisfactorily solved. The use of the medicaments available to date,such as aminosalicylates and pro-drugs thereof, steroids,immunosuppressive agents, is often restricted by the important sideeffects involved as well as by the sometime insufficient effectiveness.

Safer, more effective medicaments than those presently available aretherefore particularly needed.

Recently, the use of heparin has been suggested in the IBD parenteraltreatment: in fact, although IBD etiology has still to be clarified, itspathogenesis is somewhat clearer, and this can account for the use ofheparin in this disease.

In particular, the thrombophilic state frequently observed in ulcerativecolitis favours intravasal district coagulation, which is confirmed bythe presence of sub-mucosal microthrombosis and by vasculytic phenomenaon the mesenteral vessels; furthermore, important inflammatoryconditions are always present, which can be related with an alterationof both the immune system and the Th1/Th2 balance, which are mediated byinterleukins (IL-1), TNF and numerous other pro-inflammatory cytokines.

All these considerations suggest the presence of vascular damageassociated with, or consequent to, inflammatory conditions on an immunebase, in the pathogenesis of ulcerative colitis.

Clinical studies have confirmed the therapeutical activity of heparinadministered parenterally, usually through subcutaneous injection, inthe treatment of IBD (Aliment. Pharmacol.Ther. 1997;11:1037-1040;Inflammatory Bowel Diseases, 1997;3(2): 87-94; Gastroenterology,1996;110:A872; Gastroenterology, 1996;110. A 900; Gastroenterology,1996;110. A908, Gut, 1995;137(S2):F194; Am. J. Gastroenterol.1995;90:220-223).

In these clinical studies, heparin was always administered intravenouslyor subcutaneously, namely through the conventional administration routesof choice for heparins and other glycosaminoglycan derivatives, whichusually are not absorbed orally. Studies have been carried out foralternative administration routes to the injective one, such as the oraladministration, which is by far suitable for self-medication for use inthe antithrombotic therapy. However, heparin and low molecular weightderivatives thereof, when administered orally, are absorbed ininsufficient amounts to attain an effective concentration and usuallyonly in the first tract of intestine.

On the other hand, considering the chronic nature of IBD, the oraladministration would be much preferable, as the treatment is usuallylong-term.

Formulations studied to increase heparin absorption in thegastro-intestinal tract are described in WO-A-01/34114 andWO-A-00/48589.

According to the invention, controlled-release formulations containingheparin or low molecular weight derivatives thereof have now been found,which can be administered through the oral route and are particularlysuitable for the treatment of IBD, in that they provide the gradualrelease of heparin in the intestinal tract in corrispondence with theinflammed intestinal mucosa and therefore a rapid, effectivetherapeutical response.

The formulations of the invention have also the advantage of preventingor slowing down any degradation and depolymerization of the molecule bythe digestive juices, in the first tract of the transit of themedicament to reach the intestinal tract, where its therapeutical actionhas to be exerted.

The controlled-release compositions of the invention consist of amulti-matrix structure comprising:

-   -   a) a matrix consisting of amphiphilic compounds and lipophilic        compounds, with melting point lower than 90° C., in which the        active ingredient is at least partially englobated;    -   b) an outer hydrophilic matrix, in which the        amphiphilic/lipophilic matrix is dispersed;    -   c) optionally, other excipients.

“Heparin” herein means both unfractioned heparins of various origin, andlow molecular weight heparins, typically ranging from 1,000 to 10,000Da, such as enoxaparin, fraxiparin, dalteparin, parneparin, their saltsand/or derivatives and the like, and other glycosaminoglycans such asheparan sulfates, dermatan sulfates and hyaluronates. Preferably, thecompositions of the invention contain optionally salified heparins(sodium or calcium heparin) or low molecular weight heparins.

The compositions of the invention, containing heparin or low molecularweight heparins or other glycosaminoglycans, can be prepared with amethod comprising the following steps:

-   -   a) First, heparin is embedded in by kneading or mixing or is        coated with amphiphilic compounds, which will be precised below.        Mixing can be carried out without using solvents or with small        amounts of water-alcoholic solvents.    -   b) The matrix from a) is added in a low melting lipophilic        excipient or mixture of excipients, with heating to soften        and/or melt the excipient in which the active ingredient is thus        dispersed. The inert matrix resulting from cooling to room        temperature can be reduced in size to obtain inert matrix        granules containing the active ingredient particles.    -   c) The granules of inert+amphiphilic matrix are then mixed with        one or more hydrophilic excipients which swell in the presence        of water, thus increasing their volume to form a hydrated,        highly viscous layer in which the solvent progress is slowed        down. The mixture of powders and matrix granules is then        subjected to compression or compaction so that, when the tablet        is contacted with biological fluids, a swollen, highly viscous        layer forms, which coordinates the solvent molecules and acts as        a barrier against the penetration of the aqueous fluid inside        the new structure. Said barrier antagonizes the starting “burst        effect” deriving from the dissolution of the medicament present        inside the inert matrix, which is in turn inside the hydrophilic        matrix.

Amphiphilic compounds for use according to the invention comprise polarlipids of type I or II (lecithin, phosphatidylcholine,phosphatidyl-ethanolamine), ceramides, glycol alkyl ethers such asdiethylene glycol monomethyl ether (Transcutol®), polyoxyethylatedcastor oil, polysorbates, phosphoacetylcholine, sodium laurylsulfate,fatty acids sucroesters, polyethylene glycols.

The lipophilic matrix consists of compounds selected from unsaturatedand/or hydrogenated fatty acids and salts, esters or amides thereof;fatty acids mono-, di- or triglycerids of polyoxyethylated derivativesthereof, waxes, cholesterol derivatives, long chain alcohols or mixturesthereof, whose melting point ranges from 40° to 90° C.

If desired, a fatty acid calcium salt dispersed in an hydrophilic matrixprepared with alginic acid can be englobated inside the lipophilicmatrix, to markedly increase the hydrophilic matrix viscosity, due topenetration of the solvent until contacting the lipophilic matrixgranules dispersed therein.

According to an embodiment of the invention, a pharmaceuticalcomposition for the oral administration of heparin is obtained, bypreparing first an inert, amphiphilic matrix with high content inheparin, typically ranging from 5 to 95% w/w, through dispersion ofheparin in amphiphilic compounds, such as lecithin, other polar lipidsof type II, surfactants or diethylene glycol monoethylene; the resultingmixture is then mixed or kneaded, usually while hot, with lipophiliccompounds suitable to form an inert matrix, for example saturated orunsaturated fatty acids, such as palmitic, stearic, myristic or oleicacids, cetyl alcohol, glyceryl behenate, glyceryl palmitostearate, ormixtures thereof with other fatty acids having shorter chain, or saltsor derivatives of the cited fatty acids, alone or in combination withwaxes, ceramides, cholesterol derivatives or other apolar lipids invarious ratios, selected so that the melting or softening points of thelipophilic compounds mixtures range from 40° to 90° C.

The resulting lipophilic/amphiphilic matrix is then reduced intogranules by an extrusion and/or granulation process, or by other knownprocesses which keep the macro-homogeneous matrix dispersion structureof the starting mix.

The hydrophilic matrix to add subsequently consists of hydrogels, i.e.substances which, when passing from the anhydrous to the hydrated state,undergo the so-called molecular relaxation, characterized by a markedincrease in volume and weight following coordination of a large numberof water molecules by the polar groups present in the polymeric chainsof the hydrogels.

Examples of hydrogels for use according to the invention are compoundsselected from acrylic or methacrylic acids polymers or copolymers, alkylvinyl polymers, hydroxyalkyl celluloses, carboxyallcyl celuloses,polysaccharides, dextrins, pectins, starches and derivatives, natural orsynthetic gums, alginic acid.

Hydrophilic compounds having bio-adhesive properties can further be usedadvantageously.

The granules of lipophilic/amphiphilic matrix containing the activeingredient are mixed with the above cited hydrophilic compounds inweight ratios typically ranging from 100:0.5 to 100:20 (lipophilicmatrix: hydrophilic matrix). Part of the heparin can optionally be mixedwith the hydrophilic compounds to obtain compositions in which theactive ingredient is dispersed both in the lipophilic matrix and in thehydrophilic matrix, said compositions being preferably in the form oftablets, capsules and/or mini-matrices.

The compression of the mixture consisting of lipophilic/amphiphilicmatrix, hydrogel-forming compound and optional active ingredient notembedded in the lipophilic matrix, as well as any functional excipients,produces a structure macroscopically homogeneous throughout its volume,namely a matrix containing a dispersion of the lipophilic andamphiphilic granules in a hydrophilic matrix.

Oral solid forms such as tablets, capsules, matrix granules ormini-matrices obtainable according to the invention can be optionallysubjected to conventional coating processes with gastro-resistant films,such as methacrylic acids polymers (Eudragit®) or cellulose derivatives,such as cellulose acetophthalate and hydroxypropyl methylcellulosephthalate.

The compositions of the invention ensure the controlled release of theheparin or heparin derivative into the last part of small intestine andcolon, wherein the antithrombotic, antiinflammatory, immunomodulatingand endothelium-regulating activities of heparin on the intestinalmucosa and sub-mucosa provide an effective treatment of both activephases and relapses of ulcerative colitis, Chron's disease, sigmoiditis,proctitis -and aspecific bowel inflammatory diseases.

For the envisaged therapeutical uses, suitable doses of heparin canrange from 5 to 1000 mg per single administration, one to three times aday, with a daily dosage preferably ranging from 5 to 1000 mg.

The following examples illustrate the invention in greater detail.

EXAMPLES 1-7 Heparin Tablets for the Controlled-Release in the Colon

Quali-quantitative composition for each tablet Components Um Ex. 1 Ex. 2Ex. 3 Ex. 4 Ex. 5 Ex. 6 Ex. 7 Active ingredient Unfractioned heparin mg50 150 250 500 700 85 1000 Lipophilic component Cetyl alcohol mg 15 20Stearic acid mg 65 140 Glyceryl behenate mg 100 Hydrogenated castor oilmg 54 Glyceryl palmitostearate mg 12 White wax mg 10 Carnuba wax mg 20 1Amphiphilic component Soy lecithin mg 10 Phosphoacetylcholine 10 Sodiumlaurylsulfate 25 10 Polysorbate 10 1 10 Poe castor oil 15 1 Hydrophilicpolymer Sodium mg 50 10 carboxymethylcellulose Hydroxypropyl mg 150 20methylcellulose Hydroxypropyl cellulose mg 200 200 Hydroxyethylcellulose mg 168 Hydroxymethyl cellulose mg 200 Glidant Talc mg 10 12 1015 15 1.5 20 Anhydrous colloidal silica mg 20 28 10 5 5 0.5 10 LubricantMagnesium stearate mg 10 10 10 1 15 Hydrogenated castor oil mg 30 30 2Diluent Mannitol mg 550 Mocrocrystalline cellulose mg 225 200 Lactosemonohydrate mg 345 Dibasic calcium phosphate mg 200 218 Calciumcarbonate mg 150 Coating Acrylic polymers mg 32 32 32 32 32 3.2 32 Talcmg 15 15 15 15 15 1.5 15 Triethyl citrate mg 3.2 3.2 3.2 0.3 3.2 Dibutylphthalate mg 3.2 3.2 Titanium dioxide mg 6 6 6 6 6 0.6 6 Iron oxide mg 33 3 3 3 0.3 3 Polyethylene glycol 600 mg 1 1 1 1 1 0.1 1

EXAMPLES 8-14 Heparin Tablets for the Controlled-Release in the ColonEXAMPLES 8-14

Quali-quantitative composition per each tablet Ex. Ex. Ex. Ex. Ex.Components Um Ex. 8 Ex. 9 10 11 12 13 14 Active ingredient LMW heparinmg 100 15 250 500 700 8.5 1000 (MW range 2000-10000) Lipophiliccomponent Cetyl alcohol mg 50 20 Stearic acid mg 6.5 140 Glycerylbehenate mg 100 Hydrogenated castor oil mg 54 Glyceryl palmitostearatemg 1.2 White wax mg 10 Carnauba wax mg 20 0.1 Amphiphilic component Soylecithin mg 10 Phosphoacetylcholine 1 Sodium laurylsulfate 25 10Polysorbate 10 0.1 10 Poe. castor oil 15 0.1 Hydrophilic polymer Sodiumcarboxymethylcellulose mg 50 10 Hydroxypropyl methylcellulose mg 15 2Hydroxypropyl cellulose mg 200 Hydroxyethyl cellulose mg 168Hydroxymethyl cellulose mg 200 Glidant Talc mg 10 1.2 10 15 15 0.15 20Anydrous colloidal silica mg 20 2.8 10 5 5 0.05 10 Lubricant Magnesiumstrearate mg 10 1 10 0.05 15 Hydrogenated castor oil mg 30 30 0.2Diluent Mannitol mg 550 Microcrystalline cellulose mg 22.5 200 Lactosemonohydrate mg 345 Dibasic calcium phopshate mg 20 218 Calcium carbonatemg 150 Coating Acrylic polymers mg 32 3.2 32 32 32 0.32 32 Talc mg 151.5 15 15 15 0.15 15 Trietyl citrate mg 3.2 0.3 3.2 0.05 3.2 Dibutylphthalate mg 3.2 3.2 Titanium dioxide mg 6 0.6 6 6 6 0.06 6 Iron oxidemg 3 0.3 3 3 3 0.03 3 Polyethylene glycol 600 mg 1 0.1 1 1 1 0.02 1

EXAMPLE 15

2 Kg of sodium Parnaparin are mixed with 100 g of stearic acid, 150 g ofsodium laurylsulfate and 40 g of magnesium stearate before beingcompacted by compression. The resulting slugs are forced through agranulator fitted with a mesh screen suited to break the compactedgranules to 2 mm maximum size; then 500 g of hydroxypropylmethylcellulose, 1000 g of microcrystalline cellulose, 1000 g oflactose, 130 g of colloidal silica and 80 g of magnesium stearate areadded. After thoroughly mixing, the powders are tabletted with abiconvex tooling to unitary weight of about 500 mg. The resulting coresare then placed in a coating pan and coated with a gastro-protectivefilm containing methacrylic copolymers of type A and B, titaniumdioxide, talc, triethyl citrate, iron oxides and polyethylene glycol.The resulting tablets showed the characteristic slow dissolutionprofile, releasing the active ingredient linearly and progressively inabout 8 hours.

EXAMPLE 16

1.2 Kg of sodium Parnaparin are mixed with 50 g of stearic acid, 100 gof sodium cholate and kneaded with a solution containing an acrylicpolymer. After granulation through a 3 mm screen and subsequent drying,200 g of high viscosity hydroxypropyl methylcellulose, 50 g ofcarboxyvinyl polymer, 500 g of lactose, 500 g of microcrystallinecellulose, 80 g of colloidal silica and 70 g of magnesium stearate areadded. After thoroughly mixing, the powders are tabletted to unitaryweight of about 250 mg using a rotary tabletting machine. The resultingcores, after gastro-resistent film-coating with acrylic copolymers oftype A and B, titanium dioxide, talc, triethyl citrate, iron oxides andpolyethylene glycol, showed a progressive dissolution curve in simulatedenteral juice with about 30% of active ingredient released in the first2 hours, and at least 80% in the first 8 hours.

EXAMPLE 17

600 g of sodium Parnaparin are mixed with 20 g of stearic acid, 10 g ofwax, 25 g of soy lecithin and kneaded with a solution containing amedium-viscosity cellulose derivative. After granulation through a 2 mmscreen and subsequent drying, 200 g of sodium carboxymethyl cellulose,400 g of lactose, 550 g of microcrystalline cellulose, 50 g of colloidalsilica and 30 g of magnesium stearate are added. After thoroughlymixing, the powders are tabletted to unitary weight of about 200 mgusing a rotary tabletting machine. The resulting cores, aftergastro-resistent film-coating with acrylic copolymers of type A and B,titanium dioxide, talc, triethyl citrate, iron oxides and polyethyleneglycol, showed a progressive dissolution curve in simulated enteraljuice with less than 40% of active ingredient released in the first 2hours, and at least 80% in the first 8 hours.

1. Oral pharmaceutical compositions for the controlled release ofheparin or derivatives thereof, comprising: a) a matrix consisting ofamphiphilic compounds and lipophilic compounds with melting point lowerthan 90° C. in which the active ingredient is at least partiallydispersed; b) an outer hydrophilic matrix in which thelipophilic/amphiphilic matrix is dispersed; c) optionally, otherexcipients suitable for solid pharmaceutical forms.
 2. Compositions asclaimed in claim 1, wherein the amphiphilic compounds are polar lipidsof type I or II (lecithin, phosphatidylcholine,phosphatidylethanolamine), ceramides, glycol alkyl ethers such asdiethylene glycol monomethyl ether (Transcutol®), polyoxyethylenatedcastor oil, sodium laurylsulfate, polysorbates, phosphoacetylcholine. 3.Compositions as claimed in claim 1, wherein the lipophilic matrixconsists of compounds selected from unsaturated and/or hydrogenatedfatty acids, the salts, esters or amides thereof, fatty acids mono-, di-or triglycerids, polyoxyethylated derivatives thereof, waxes,cholesterol derivatives, long chain aliphatic alcohols.
 4. Compositionsas claimed in claim 1, wherein the hydrophilic matrix consists ofhydrogel-forming compounds.
 5. Compositions as claimed in claim 1,wherein the hydrophilic matrix consists of compounds selected fromacrylic or methacrylic acids polymers or copolymers, alkyl vinylpolymers, hydroxyalkyl celluloses, carboxyalkyl celluloses,polysaccharides, dextrins, pectins, starches and derivatives, alginicacid, natural or synthetic gums.
 6. Compositions as claimed in claim 1,in the solid form with gastro-resistant coating.
 7. Compositions asclaimed in claim 6, wherein the gastro-resistant coating consists ofmethacrylic acid polymers or cellulose derivatives.
 8. Compositions asclaimed in claim 1, wherein the active ingredient is contained entirelyin the inert/amphiphilic matrix and the pharmaceutical form toadminister is in the form of tablets, capsules or mini-matrices. 9.Compositions as claimed in claim 1, wherein the active ingredient isdispersed both in the hydrophilic matrix and in thelipophilic/amphiphilic matrix, in the form of tablets, capsules ormini-matrices.
 10. Compositions as claimed in claim 1, wherein thecompounds which form the hydrophilic matrix have bio-adhesiveproperties.
 11. Compositions as claimed in claim 1, wherein the activeingredient is selected from heparin, sodium heparin, calcium heparin,sodium parnaparin, heparin with molecular weight ranging from 1,000 to10,000 Da, heparan sulfates, dermatan sulfates, hyaluronates. 12.Compositions according to claim 11, wherein the active ingredient issodium parnaparin.
 13. A process for the preparation of the compositionsof claim 1, which comprises: a) kneading or mixing the heparin with theinert and amphiphilic compounds in the absence of solvents or inwater-alcoholic solvents; b) mixing the granules from step a) with thehydrophilic excipients and subsequent compression and compaction; c)optionally, gastro-protective film-coating of the oral solid forms fromstep b).